OVERALL: SUMMARY/ABSTRACT Michelle M. Mielke, Ph.D. Aging-associated physical and cognitive decline and Alzheimer's disease (AD) are conditions that affect men and women differently across their lifespan. There are important sex and gender differences for these conditions, including risk factors, manifestations, response to treatments, morbidity, and mortality. The overarching theme of the Mayo Clinic Specialized Center of Research Excellence (SCORE) on Sex Differences is to investigate how abrupt loss of ovarian hormones, caused by bilateral salpingo-oophorectomy (BSO) prior to natural menopause, affects overall aging, physical and cognitive function, and risk for AD pathophysiology. Given the large number of aging women with a history of premenopausal BSO, there is an urgent need to understand the long-term physical and cognitive outcomes. In addition, we need new evidence to empower women considering prophylactic BSO to make more informed decisions in the future. The central hypothesis of our SCORE renewal is that the abrupt endocrine disruption caused by premenopausal BSO will accelerate pathological aging processes that manifest as reductions in physical and cognitive function and in AD pathophysiology. This hypothesis will be tested through three inter-related translational projects, which are supported by three inter-dependent Cores. Our interdisciplinary translational approach using both humans (Projects 1 and 2) and mice (Project 3) provides the foundation to: 1) establish the effects of abrupt endocrine disruption in women, 2) develop a more complete understanding of the biological mechanisms involved, 3) devise a targeted approach to identify and mitigate the adverse outcomes, 4) design future studies to mechanistically test whether targeting senescent cells mitigates the effects of accelerated aging in these women, and 5) empower women considering prophylactic BSO to make more informed decisions. Our rigorous approach is supported by an experienced leadership team through the Leadership Administrative Core, by a Resource Support Core - Clinical that will provide financial and operational efficiency for participant recruitment, and by a Career Enhancement Core that will provide career enrichment, leadership training, and funds to support ancillary studies of the main projects. These resources will stimulate new interest in sex differences and women's health. The Mayo Clinic SCORE will serve as a vital hub for education and dissemination of innovative sex-based translational research methods, results, and best practices. Our integrated approach for research, training, and education is consistent with the goals of the SCORE on Sex Differences RFA, and assures continuing research in areas of women's health and sex differences by training the work force of the future.